OP0074 RADIOGRAPHIC AND PAIN OUTCOMES FROM A PHASE 3 EXTENSION STUDY EVALUATING THE SAFETY AND EFFICACY OF LORECIVIVINT IN SUBJECTS WITH SEVERE OSTEOARTHRITIS OF THE KNEE (OA-07): SINGLE BLIND AND CROSSOVER RESULTS
Authors: Y. Yazici, C. Swearingen, V. Lopez, J. Britt, S. Kennedy, J. Tambiah, T. Mcalindon
Journal: Annals of the Rheumatic Diseases (2023)

<h3>Background</h3> Knee osteoarthritis (OA) is a common joint disorder associated with pain, disability, and joint damage. An unmet need remains for safe, efficacious treatments for symptoms and disease modification. Lorecivivint (LOR), a novel intra-articular (IA) CLK/DYRK inhibitor thought to modulate Wnt and inflammatory pathways, has previously appeared safe, demonstrated patient-reported outcome (PRO) improvements compared with placebo (PBO), and maintenance of radiographic medial joint space width (JSW). <h3>Objectives</h3> An ongoing extension study, OA-07 (NCT04520607), continues to evaluate LOR safety and efficacy with primary and secondary efficacy outcomes of medial JSW (mm) and Pain Numerical Rating Scale (NRS [0-10]), WOMAC Pain [0-100], and WOMAC Function [0-100], respectively. Preliminary data up to 36 months are reported. <h3>Methods</h3> Participants with structurally advanced (medial JSW 1.5-4 mm) knee OA who completed the parent Phase 3 LOR trial were enrolled into OA-07. At the beginning of the single-blind (participants and investigators blinded) extension Year 1, participants received a repeat injection according to the initial randomized treatment (LOR or PBO). In Year 2 and annually thereafter, all participants (LOR and PBO) received an open-label 0.07 mg, IA LOR injection. The extension trial commenced in July 2020 with clinic visits every six months. Baseline-adjusted ANCOVA was used to estimate difference between LOR and PBO on outcomes using the OA-07 baseline. Treatment effect at Month 36 was estimated using marginal comparison from baseline-adjusted ANCOVA to a last PBO observation prior to crossover for LOR only. Concordance between OA-07 baseline-adjusted medial JSW change and pain response was conducted for 36 month completers using logistic regression. <h3>Results</h3> 277 subjects (mean age 61.0 ± 8.2 years, BMI 31.8 ± 4.9 kg/m<sup>2</sup>, female 62.8%, KL3 45.5%, 67.1% bilaterally symptomatic, mean baseline medial JSW 2.63 ± 0.69 mm, 68.6% medial JSW &lt; 3 mm) were enrolled. LOR appeared safe and well-tolerated, consistent with its previously observed safety profile. At 24 months, the LOR treatment arm showed reduced medial JSW loss compared to placebo: LOR -0.11 (± 0.05) mm (n=111) vs. PBO -0.20 (± 0.05) mm (n=119) (Δ=0.09 mm, 95% CI [-0.06, 0.23], <i>P</i>=0.246). The 36-month LOR completers demonstrated continued improvement with LOR (n=21) medial JSW change of 0.03 (± 0.11) mm vs. PBO (n=28) -0.30 (± 0.09) mm (Δ=0.33 mm, 95% CI [0.05, 0.62], P=0.023) at 24 months. At 36 months, LOR medial JSW change was +0.19 (± 0.14) mm (n=23), a difference of -0.49 mm (<i>P</i>=0.019) in medial JSW with LOR in comparison to the last PBO measure before crossover at 24 months (Figure 1). Average change from extension baseline to 24 months in Pain NRS was -0.25 (± 0.19) for LOR (n=121) compared to 0.09 (± 0.19) for placebo (n=130) (Δ=-0.34, 95% CI [-0.87, 0.19], <i>P</i>=0.207). Similar trends were seen for LOR treatment effect over PBO at 24 months for WOMAC Function Δ=-4.90 (95% CI [-9.92, 0.13], <i>P</i>=0.056) and WOMAC Pain Δ=-5.18 (95% CI [-10.28, -0.08], <i>P</i>=0.047). At 36 months, open-label IA injection of LOR (n=35) showed additional Pain NRS improvements with change from OA-07 baseline of -0.91 (±0.34) and cross-over participants from PBO to LOR (n=45) showed improvement of -0.43 (±0.30). Good concordance was shown between change in medial JSW and at least a 20% improvement in Pain NRS at 36 months (n=20, AUC=0.719). <h3>Conclusion</h3> LOR continues to appear safe and well tolerated. A potential benefit of LOR 0.07 mg compared with PBO in medial JSW is observed 12 months after the extension baseline (second overall) injection, which persisted and improved in those who have completed an additional 12 months (total 36 months, after three injections) and in PBO participants who crossed over to active treatment with LOR. Potential LOR benefit compared to PBO is also seen across PROs along with preliminary good concordance data between medial JSW and pain improvement. This study is ongoing. <h3>REFERENCES:</h3> NIL. <h3>Acknowledgements:</h3> NIL. <h3>Disclosure of Interests</h3> Yusuf Yazici Shareholder of: Biosplice Therapeutics, Employee of: Biosplice Therapeutics, Christopher Swearingen Shareholder of: Biosplice Therapeutics, Employee of: Biosplice Therapeutics, Victor Lopez Shareholder of: Biosplice Therapeutics, Employee of: Biosplice Therapeutics, Jon Britt Shareholder of: Biosplice Therapeutics, Employee of: Biosplice Therapeutics, Sarah Kennedy Shareholder of: Biosplice Therapeutics, Employee of: Biosplice Therapeutics, Jeymi Tambiah Shareholder of: Biosplice Therapeutics, Employee of: Biosplice Therapeutics, Timothy McAlindon Consultant of: Biosplice Therapeutics, Grant/research support from: Biosplice Therapeutics.